As it is universally known, various proteases including trypsin and chymotrypsin exist in the body. While these proteases take important roles in the body such as digestion, defense mechanism, blood coagulation and fibrinolysis and the like, it has been revealed by previous studies that they also cause diseases and troubles directly or indirectly. Shock, pancreatitis, disseminated intravascular coagulation syndrome (DIC) and the like are known as typical diseases which are caused by abnormal activation of proteases.
Various types of protease inhibitors have been used with the aim of treating such protease-related diseases. The protease inhibitors so far used as pharmaceutical drugs for the treatment of these diseases are divided into two groups, namely chemically synthesized compounds and natural substances. In most cases, chemically synthesized compounds are applicable to oral administration and have a broad enzyme inhibition spectrum, while each of the natural substances inhibits each own specific protease and is possessed of other functions than its enzyme inhibition function, such as a cell growth enhancing activity and the like.
Inhibition spectrum of each natural protease inhibitor is greatly related to the kinds and sequence of amino acids on its active center. For example, trypsin type enzymes are inhibited by a protease inhibitor when an amino acid of a principal position P.sub.1 on the active center of the protease inhibitor is Lys or Arg, chymotrypsin type enzymes are inhibited when the P.sub.1 amino acid is Phe or Tyr and elastase type enzymes are inhibited when the P.sub.1 amino acid is Ala, Ser or Val (Laskowski M., Jr., Biochem. Pharmacol., vol.29, pp.2089-2094, 1980). In consequence, it is assumed that inhibition spectrum of a natural protease inhibitor can be changed by substituting an amino acid which is a composing element of the active center of the inhibitor. Such an approach has already been applied to several natural protease inhibitors. For example, Brinkmann et al. have reported that chymotrypsin inhibition activity of aprotinin was improved when positions P.sub.1 and P'.sub.2 on the active center of aprotinin were substituted by a hydrophobic amino acid such as Phe, Tyr, Leu or the like (Thomas Brinkmann et al., Eur. J. Biochem., vol.202, pp.95-99, 1991). In addition, Fritz et al. have prepared a substance by substituting an amino acid on the active center of Bikunins (HI-30) by other amino acid, and have measured its elastase- and trypsin-inhibiting activities (Japanese Patent Application Kokai No. 3-255099, 1991; European Patent EP401508, 1990).
Since changes in the properties of a protease inhibitor caused by such an amino acid substitution exert influence not only upon its enzyme inhibition spectrum but also upon its route of administration, pharmacological function and the like, it is important to develop various types of protease inhibitors having such new characteristics for use in the treatment of diseases and to use the new inhibitors according to the conditions of each disease to be treated.